It is generally the case that organic compounds must be synthesized as pure substances through well-planned reactions and scrupulous separation/purification. In fields such as drug discovery, catalyst design and new material development, tens of thousands of organic compounds must be synthesized and tested to discover a few active ones. In the pharmaceutical industry, for example, synthesizing large numbers of compounds in the traditional way is ineffective relative to the rapid emergence of new biological targets. A major factor limiting the productivity of orthodox solution (liquid) phase organic synthesis is the time consuming process of purification. High throughput organic synthesis, therefore, preferably integrates organic reactions with rapid purification/separation procedures.
Recently, fluorous synthetic and separation techniques have attracted the interest of organic chemists. In fluorous synthetic techniques, reaction components are typically attached to fluorous groups or tags such as perfluoroalkyl groups to facilitate the separation of products. Organic compounds are readily rendered fluorous by attachment of an appropriately fluorinated phase label or tag. In general, fluorous-tagged molecules partition preferentially into a fluorous phase. This fluorous phase is typically insoluble in organic or inorganic solvents under standard reaction conditions. This characteristic of fluorous compounds has lead to the development of fluorous biphasic catalysis (I. T. Horvath and J. Rabai, Science, 1994, 266, 72). Fluorous biphasic catalysis provides a simple solution to the product/reagent or product/catalyst separation problems inherent in chemical systems. By utilizing a fluorous reagent or catalyst, separation of the fluorous reaction components from the organic reaction components is accomplished via a fluorous phase/organic phase liquid/liquid or liquid/solid separation protocol wherein the fluorous reagent or catalyst selectively partitions into the fluorous phase and the organic products partition into the organic phase. Fluorous separation techniques include, but are not limited to, fluorous liquid-liquid extraction, fluorous solid phase extraction, and fluorous chromatography. See, for example, Danielson, N. D. et al., “Fluoropolymers and Fluorocarbon Bonded Phases as Column Packings for Liquid Chromatography,” J. Chromat., 1991, 544, 187-199; Curran, D. P. “Fluorous Reverse Phase Silica Gel. A New Tool for Preparative Separations in Synthetic Organic and Organofluorine Chemistry,” Synlett, 2001, 9, 1488; Curran D. P., “Fluorous Techniques for the Synthesis of Organic Molecules: A Unified Strategy for Reaction and Separation.” In: Stimulating Concepts in Chemistry (M. Shibasaki, J. Fraser Stoddart and F. Vögtle, eds.), Wiley-VCH, Weinheim, 2000, 25. Several fluorous reaction and separation techniques are disclosed, for example, in U.S. Pat. Nos. 6,156,896; 5,859,247 and 5,777,121, the disclosures of which are incorporated herein by reference in their entirety. In addition, several fluorous reaction and separation techniques are disclosed in U.S. patent application Ser. Nos. 09/506,779; 09/565,087; 09/583,247; 09/932,903; 09/977,944 and 10/094,345, the disclosures of which are incorporated by reference herein in their entirety.
However, the use of fluorous and perfluorous liquids as reaction or separation solvents may have potential drawbacks. It is well known that low molecular weight fluorocarbons (freons) are greenhouse gases whose release into the atmosphere has environmental consequences. While most fluorous solvents are typically higher molecular weight fluorocarbons, they typically have long environmental half-lives and their environmental impact is less well known. In addition, fluorinated solvents are typically more expensive than their organic counterparts. Therefore, it would be desirable to have a system with the separation advantages of fluorous components without the use of fluorous reaction and/or separation solvents.
Recent reports demonstrate some advances that limit the use of fluorous solvents while still retaining the advantages of fluorous separation techniques. Yamamoto, et al. have reported a fluorous catalyst system that uses liquid/solid extraction to remove the fluorous catalyst from the reaction mixture by precipitation of the catalyst at low temperature (K. I. Ishihara, S. Kondo, H. Yamamoto, Synlett, 2001, 9, 1371). This method has limited application because it requires the use of fluorous catalysts having specific inherent solubility characteristics such that the catalyst will precipitate in solid form for removal. Eckert, et al. have disclosed a method which eliminates the use of fluorous solvents, utilizing the increased solubility of fluorous compounds in organic solvents saturated with dissolved gaseous CO2 (C. A. Eckert, P. G. Jessop, C. L. Liotta, International Patent Application No. PCT/US02/17110). This method requires the use of gaseous CO2 under pressures in the range of 30-300 bar, and reaction equipment capable of withstanding pressurization. Accordingly, this method requires the use of specialized equipment that is relatively costly and more hazardous than other known fluorous reaction/separation techniques. Vaughan, et al. have disclosed a fluorous biphasic catalyst wherein the catalyst is supported on functionalized polymeric beads (J. F. S. Vaughan, M. G. Pellatt, J. Sherrington, E. G. Hope, U.S. patent application Ser. No. U.S. 2003/0148878 A1, and International Patent Application No. PCT/EP01/06676). However, this method still requires the use of fluorous reaction solvents to facilitate the reaction, albeit in reduced volumes.
By combining reaction and separation features, the present invention also has advantages over standard fluorous solid phase extractions (spe), which pertain only to the separation part of a chemical synthesis. In fluorous spe's, a crude product after completion of a chemical reaction is typically added to fluorous silica gel and eluted with a suitable fluorophobic solvent followed by a fluorophilic solvent. Sometimes, the silica gel is added to the reaction mixture after the reaction is complete, and then the slurry is loaded directly (or evaporated and then loaded) onto a fluorous silica column to complete the spe with the usual fluorophobic and fluorophilic solvent extractions. Compared to the simple solid-liquid separation techniques used in the present invention, spe uses much more solvent and fluorous silica gel, is more time consuming and expensive, and does not allow for the conveniences and advantages of having supports present during the reaction.
It would therefore be desirable to develop methods that incorporate the benefits of fluorous biphasic reaction/catalysis processes, i.e. ready separation of fluorous reagents and/or catalysts from non-fluorous reaction components, while not requiring the use of fluorous solvents, pressurized reaction environments and/or specific precipitation characteristics of the fluorous reaction component.